Atopic allergic reactions are of the immediate hypersensitivity type as opposed to delayed hypersensitivity reactions, the latter being involved in such things as tuberculin sensitivity, transplant rejection, contact dermatitis and the like. Commonly recognized clinical conditions known to be at least in part due to atopic immediate hypersensitivity reactions, include seasonal and perennial allergic rhinitis (hay fever) and asthma, anaphylaxis, urticaria, conjunctivitis, angioaedema, eczema, various food and drug reactions and insect sting reactions. The substances most frequently responsible for atopic allergic reactions are plant pollen, animal feathers and danders, dust, milk and wheat, whether inhaled or injected. Atopic hypersensitivity is found in man, dog and other animals although its occurrence is exceptionally found in the lower animals.
Atopic (immediate hypersensitivity) reactions are characterized by the immunopathologic mechanism, the elements of which are: (1) a specific immunoglobulin (antibody; IgE in man, or homocytotropic antibody in the rat) is produced; (2) it is fixed to the surface of a target cell; (3) an antigen or allergin combines with the cell-bound antibody, which (4) induces release or one or more pharmacologic mediators, which in turn (5) induces symptoms of clinical disease such as increased vascular permeability, smooth muscle contraction, mucous gland hypersecretion, leukotaxis (especially eosinophilotaxis) and irritation of sensory nerve endings.
A compound which will interfere with the antigen-IgE reaction to prevent the release of mediators from the mast cell, or permit a non-productive antigen-antibody reaction without release of mediators, of necessity blocks the atopic allergic reaction thereby avoiding the resultant changes which are symptomatic of the disease.
The presence of antibodies associated with atopic reactions in the host serum is established by the passive sensitization of the skin of a normal recipient, after injection of serum from a sensitized host into a skin site followed by injection of antigen into the same area 24 hours later, resulting in a local hive. This is commonly referred to as the Prausnitz-Kustner (P-K) reaction.
The antibody associated with atopic hypersensitivity possesses distinctive features in that it does not in all forms precipitate with its antigen, fails to pass the placenta from mother to fetus, has special affinity for the skin, frequently lacks specificity toward an individual antigen in an individual sensitized by a variety of antigenic factors and is usually labile at about 56.degree. C. after 2 hours.
The homocytotropic antibody found in or induced in the rat is related in function and reaction to immunoglobulin E (reagin or IgE) found in the human. The correlation between homocytotropic antibody in the rat and IgE in the human has been established through the common effects obtained from chemical reactions, immunological reactions and drug responses in the two species hosting those antibodies. In the human, reagin is the antibody responsible for atopic immediate hypersensitive reactions. In the rat, the homocytotropic antibody is responsible for atopic immediate hypersensitive reactions.
In theory, reagin influences the cell membrane of a mast cell by reacting with an antigen, to initiate the reaction(s) within the mast cell which ultimately releases a mediator such as Bradykinin, SRS-A (slow reacting substance-A), histamine, and other unknown substances. The mediator effects a change in surrounding cell wall permeability permitting a rapid change in flow or exudance of mediator(s) from the cells, resulting in an allergic attack symptom. The various methods commonly employed to relieve the symptoms of allergic attack, none of which are considered to be quite acceptable, are to (1) avoid attack by the antigen, (2) block the production of antibody with an immunosuppressant, (3) block the action of the mediators on the cell under attack by administration of anti-histamines, anti-5-hydroxy-tryptamine (5-HT) or anti-inflammatories, or (4) stimulate and cell under attack to negate the action of the mediator through the action of bronchodilators such as Isoprel.RTM. or a Xanthine.
The only commercial compound known to date to operate as an anti-allergic primarily by blocking reaction(s) within the mast cells, thereby preventing the production and release of mediators, is disodium cromoglycate (INTAL.RTM.).
Disodium cromoglycate and compounds of that class are preventative in the sense that they must be administered to the sensitized animal prior to the allergic attack to be effective. They are not effective after the mediators have been released from the mast cells. Hence, their function is in preventing the release of mediators and/or a productive antibody-antigen reaction. As such, the rat PCA test (measuring the effect of mediator release) may be used to establish a compound as effective for all atopies because it establishes the diminished mediator release values in terms of the decrease in allergic response of the animal. The rat PCA test establishes the extent of mediator release from mast cells located in the rodent skin as a factor of the diminished effect on the skin of the test animal in relationship to the control animals.
The rat PCA (passive cutaneous anaphylaxis) test provides a classic procedure for evaluating the efficacy of drugs of the INTAL class relative to the response of the standard test animal resulting from antigen antibody interaction and mediator release. Extrapolation from an effect on the homocytotropic antibody of the rat to an effect on reaginic antibody (IgE) in the human is proper because of the well established relationship between these antibodies.
With knowledge of the mechanism of activity of INTAL in blocking the production of chemical mediators resulting from an antigen-antibody reaction and the variety of confirmed activities of INTAL in controlling or preventing immediate hypersensitivity reactions in man, as well as the close relationship between the rat homocytotropic antibody and IgE in the human, coupled with the fact that INTAL is the standard now used in the field for evaluating the efficacy of new anti-allergic compounds for atopic allergic reactions via the rat PCA test must lead to the practical conclusion that compounds which are active in the rat PCA test can, with very reasonable assurance, be projected as active anti-allergic agents in man, dog, etc.
As new anti-allergics are being developed, their activity mechanism is related to that of INTAL as the standard because of its known activity in man and its activity in the rat PCA test. In this regard see Pfister et al., J. Med. Chem., vol. 15, No. 10, pp. 1032-1035 (1972); Broughton et al., Nature, vol. 251, pp. 650-652, Oct. 18, 1971; and Assem et al., British Med. Journal, Apr. 13, 1974, pp. 93-95.